Effects of vinyl substitutions on resonance Raman spectra of (bacterio)chlorophylls

Soret resonance and Qy preresonance Raman spectra are reported and compared for a series of (bacterio)chlorophylls. Chlorophyll a, 2-acetylchlorophyll a, bacteriochlorophyll a and 2-vinylbacteriochlorophyll a were studied in the non-protic solvent tetrahydrofuran. These experiments were designed to identify Raman bands corresponding to the stretching mode(s) of the vinyl group at the C-2 position of ring I of chlorophyll a and 2-vinylbacteriochlorophyll a, and to ascertain whether additional bands corresponding to Ca Cm and/or Cb Cb vibrations could be observed in the 1615-1660 cm-1 region. Raman spectra of chlorophyll a and 2-vinylbacteriochlorophyll a exhibit a 1625 cm-1 band, which is absent from the Raman spectra of 2-acetylchlorophyll a and bacteriochlorophyll a. It is assigned to the vC2a C2b mode of the vinyl group. No other band can be definitively assigned to any mode predominantly arising from vinyl motions. The acetyl-containing molecules 2-acetylchlorophyll a and bacteriochlorophyll a give rise to a ca. 1070 cm-1 band, which appears to be related to the presence of the acetyl substituent. The 1615-1660 cm-1 region of the Raman spectra of all four derivatives did not contain any additional band which could be ascribed to modes involving the vCa Cm and/or Cb Cb coordinates

Arzneistofftarget-5-Lipoxygenase : ein neuer Enzymaktivierungsweg mit Einfluss auf die Wirksamkeit von Inhibitoren

Leukotriene (LT) sind bioaktive Lipidmediatoren, die in einer Vielzahl von Entzündungskrankheiten wie z.B. Asthma, Psoriasis, Arthritis oder allergische Rhinitis involviert sind. Des Weiteren spielen LT in der Pathogenese von Erkrankungen wie Krebs, Osteoarthritis oder Atherosklerose eine Rolle. Die 5-Lipoxygenase (5-LO) ist das Enzym, das für die Bildung von LT verantwortlich ist. Aufgrund der physiologischen Eigenschaften der LT, ist die Entwicklung von potentiellen Arzneistoffen, welche die 5-LO als Zielstruktur besitzen, von erheblichem Interesse. Die Aktivität der 5-LO wird in vitro durch Ca2+, ATP, Phosphatidylcholin und Lipidhydroperoxide (LOOH) und durch die p38-abhängige MK-2/3 5-LO bestimmt. Inhibitorstudien weisen darauf hin, dass der MEK1/2-Signalweg ebenfalls in vivo an der 5-LO Aktivierung beteiligt ist. Hauptziel dieser Arbeit war es zu untersuchen, welche Rolle der MEK1/2-Signalweg bei der Aktivierung der 5-LO besitzt und welchen Einfluss der 5-LO Aktivierungsweg auf die Wirksamkeit potentieller Inhibitoren hat. „In gel kinase“ und „In vitro kinase“ Untersuchungen zeigten, dass die 5-LO ein Substrat für die Extracellular signal-regulated kinase (ERK) und MK-2/3 darstellt. Der Zusatz von mehrfach ungesättigten Fettsäuren (UFA), wie AA oder Ölsäure, verstärkte den Phosphorylierungsgrad der 5-LO sowohl durch ERK1/2 als auch durch MK-2/3. Die genannten Kinasen sind demnach auch für die 5-LO Aktivierung durch natürliche Stimuli verantwortlich, die den zellulären Ca2+-Spiegel kaum beeinflussen. Daraus ist ersichtlich, dass die Phosphorylierung der 5-LO durch ERK1/2 und/oder MK-2/3 einen alternativen Aktivierungsmechanismus neben Ca2+ darstellt. Ursprünglich wurden Nonredox-5-LO-Inhibitoren als kompetitive Wirkstoffe entwickelt, die mit AA um die Bindung an die katalytische Domäne der 5-LO konkurrieren. Vertreter dieser Inhibitoren, wie ZM230487 und L-739,010, zeigen eine potente Hemmung der LT-Biosynthese in verschiedenen Testsystemen. Sie scheiterten jedoch in klinischen Studien. In dieser Arbeit konnten wir zeigen, dass die Wirksamkeit dieser Inhibitoren vom Aktivierungsweg der 5-LO abhängig ist. Verglichen mit 5-LO Aktivität, die durch den unphysiologischen Stimulus Ca2+-Ionophor induziert wird, erfordert die Hemmung zellstress-induzierter Aktivität eine 10- bis 100-fach höhere Konzentration der Nonredox-5-LO-Inhibitoren. Die nicht-phosphorylierbare 5-LO Mutante (Ser271Ala/Ser663Ala) war wesentlich sensitiver gegenüber Nonredox-Inhibitoren als der Wildtyp, wenn das Enzym durch 5-LO Kinasen aktiviert wurde. Somit zeigen diese Ergebnisse, dass, im Gegensatz zu Ca2+, die 5-LO Aktivierung mittels Phosphorylierung die Wirksamkeit der Nonredox-Inhibitoren deutlich verringert. Des Weiteren wurde das pharmakologische Profil des neuen 5-LO Inhibitors CJ-13,610 mittels verschiedener in vitro-Testsysteme charakterisiert. In intakten PMNL, die durch Ca2+-Ionophor stimuliert wurden, hemmte die Substanz die 5-LO Produktbildung mit einem IC50 von 70 nM. Durch Zugabe von exogener AA, wird die Wirkung vermindert und der IC50 des Inhibitors steigt an. Dies deutet auf eine kompetitive Wirkweise hin. Wie die bekannten Nonredox-Inhibitoren, verliert auch CJ-13,610 seine Wirkung bei erhöhtem zellulärem Peroxidspiegel. Der Inhibitor CJ-13,610 zeigt jedoch keine Abhängigkeit vom Aktivierungsweg der 5-LO. Grundsätzlich ist es also von fundamentaler Bedeutung bei der Entwicklung von neuen Arzneistoffen, die zellulären Zusammenhänge, insbesondere die Regulierung der Aktivität von Enzymen, zu kennen. Wie in dieser Arbeit gezeigt, hat die Phosphorylierung der 5-LO einen starken Einfluss auf die Regulation der 5-LO Aktivität und eine elementare Wirkung auf die Hemmung des Enzyms durch verschiedene Wirkstoffe

Who Prices Locally? Survey Evidence of Swiss Exporters

Survey information on Swiss exporters is used to test the hypothesis that firm-specific factors, in particular firm size, are important determinants of pricing--to-market (PTM). The survey asked exporters whether they set different prices across markets and, if so, whether price segmentation occurred because of pricing conditions in the local market or other factors. The empirical analysis is based on a probit model that regresses a binary-choice variable of PTM on firm size and other control variables. The main empirical finding is that firm size and PTM are positively and significantly correlated. A further result is that while firms whose main export market is in the Euro area are less likely to engage in PTM, firm size plays a bigger role for them. These results are robust across different PTM classifications, regression specifications, export destinations, and industrial sectors.Pricing to markets, local currency pricing, firm size

Who Prices Locally? Survey Evidence of Swiss Exporters

Survey information on Swiss exporters is used to test the hypothesis that firm-specific factors, in particular firm size, are important determinants of pricing-to-market (PTM). The survey asked exporters whether they set dif- ferent prices across markets and, if so, whether price segmentation occurred because of pricing conditions in the local market or other factors. The empirical analysis is based on a probit model that regresses a binary-choice variable of PTM on firm size and other control variables. The main empirical finding is that firm size and PTM are positively and significantly correlated. A further result is that while firms whose main export market is in the Euro area are less likely to engage in PTM, firm size plays a bigger role for them. These results are robust across different PTM classifications, regression specifications, export destinations, and industrial sectors.Pricing to markets, local currency pricing, .rm size

Biotransformation of caffeoyl quinic acids from green coffee extracts by Lactobacillus johnsonii NCC 533

Acknowledgements The authors are grateful to Nicole Page-Zoerkler and Olivier Mauroux for their technical assistant. We thank David Pridmore and Kimo Makkinen for critical reading of this manuscript.Peer reviewedPublisher PD

Short communication : Mouse skin papilloma formation by chronic dermal application of 7,12-dimethylbenz[a]anthracene is not reduced by diet restriction

No abstract availabl

Mouse skin papilloma formation by chronic dermal application of 7, 12-dimethylbenz[a] anthracene is not reduced by diet restriction

Diet restriction has repeatedly been shown to reduce the incidence of spontaneous and chemically induced tumors in rodents. However, no conclusive data are available to show whether carcinogenesis by chronic exposure to a genotoxic agent can also be retarded. In this study, diet restriction to 70% was investigated for a protective effect on the formation of skin papilloma in male NMRI mice treated twice weekly with 20 nmol 7,12-dimethylbenz(a)anthracene (DMBA). Rather surprisingly, no protection was seen. Both time of onset of papilloma formation (13 weeks in both groups) and time of 50% cumulative incidence (t50; 17.5 and 18 weeks) were similar in the unrestricted and the restricted group. In contrast, a clearly protective elTect was found in mice initiated with 100 nmol DMBA and promoted twice weekly with 2.5 nmol 12-O-tetradecanoylphorbol-13-acetate: the onset of papilloma formation increased from 7 to 11.5 weeks, the t50 was shifted from 8.5 to 19 weeks. Diet restriction, therefore, was not protective under conditions of chronic exposure to a genotoxic carcinogen. It cannot be considered a universal measure of cancer preventio

Shear thickening, temporal shear oscillations, and degradation of dilute equimolar CTAB/NaSal wormlike solutions

The rheological characterization of dilute and semi-dilute equimolar cetyltrimethylammonium bromide and sodium salicylate solutions is reported, including their linear and nonlinear responses. Start-up experiments and direct birefringence measurements suggest that even at a concentration of as low as 1.0 mM, temporal shear oscillations occur at low shear rates. At concentrations above 10 mM, those low-stress structures vanish and give way to shear-thickening and shear-banding behaviors as seen for other semi-dilute surfactant solutions. Also, the degradation of these solutions after exposure to rubber pump tubing is covere

DNA adducts, cell proliferation and papilloma latency time in mouse skin after repeated dermal application of DMBA and TPA

The mouse skin tumor model was used to investigate whether the level of DNA adducts and/or the rate of cell division in the epidermis are indicators of the risk of cancer formation for an individual in an outbred animal population. A high risk was considered to be reflected by a short latency period for the appearance of a papilloma. Female NMRI mice were treated twice weekly with 2.5 nmol 7,12-dimethylbenz[a]anthracene (DMBA) and 3 nmol 12-O-tetradecanoylphorbol-13-acetate (TPA) and the appearance of papillomas was registered. The first papilloma appeared after 7.5 weeks. After 17 weeks, when 12 of 14 mice had at least one papilloma, an osmotic minipump delivering 5-bromo-2'-deoxyuridine (BrdU) was implanted into each mouse for 24 h. The mice were killed after 24 h and the epidermis was analyzed for DMBA-nucleotide adducts by 32P-postlabeling, for the cell number per unit skin length, and for the labeling index for DNA synthesis. Unexpectedly, DMBA-nucleotide adduct levels were highest in those animals which showed the longest latency periods. Adduct levels were negatively correlated with the labeling index, indicating that dilution of adducts by cell division was a predominant factor in determining average adduct concentrations. Individual tumor-latency time was not correlated with either cell number or labeling index. This could be due to the fact that the measurements only provided averaged data and gave no information on the specific situation in clones of premalignant cells. Under the conditions of this assay, therefore, neither DNA adduct levels nor information on the average kinetics of cell division had a predictive value for the individual cancer risk within a group of outbred animals receiving the same treatmen